Proteolipid protein (PLP) is the major protein component of CNS myelin and appears to be a major target of immune responses both in murine models of experimental autoimmune encephalomyelitis (EAE) and perhaps in human multiple sclerosis (MS). A chronic-relapsing form of EAE (R-EAE) is induced in inbred SJL/J mice following either active immunization with intact PLP or the major encephalitogenic determinant of the PLP molecule which encompasses amino acids 139-151 (PLP1 39-151(S)), or the adoptive transfer of T cell lines/clones specific for the PLP1 39-151(S) epitope. PLP-induced R-EAE follows a relapsing-remitting course of paralysis and is characterized histologically by perivascular mononuclear cell-rich infiltrates of the white matter of the central nervous system (CNS) and areas of acute and chronic demyelination. The well-understood genetics of the murine host and the similarities in both clinical course and histopathology of murine R-EAE and MS make it an ideal animal model for the study of immunoregulatory aspects of oral tolerance. We will address the cellular and molecular mechanisms of oral tolerance induction by the intragastric (i.g.) administration of PLP. This will include examining the effects of oral PLP on phenotype, effector/regulatory role, fine tolerogenic epitope specificity, cytokine gene expression, and cytokine protein secretion profile of peripheral, CNS, and gut T cell-mediated immune responses, as well as antiPLP antibody responses during the induction and relapsing episodes of active PLP/PLP139-151(5)-induced R-EAE in SJL/J mice. These studies will allow us to temporally compare the cellular and molecular effects of oral antigen administration, either alone or followed by neuroantigen immunization on peripheral, CNS, and gut immune responses. A major emphasis will be to determine the relative contributions of specific regulatory T cell populations and/or clonal deletion/anergy, induced by i.g. administration of PLP and PLP peptides, to the prevention and treatment of clinical disease, and to the regulation of accompanying neuroantigen-specific T cell responses. In addition, the role of gastrointestinal proteolytic enzymes in generating efficient oral tolerance will be determined by testing the effects of specific inhibitors of digestive endopeptidases (trypsin, chymotrypsin, elastase), alone or in combination, on inhibition of EAE induction. These studies should lead to a better understanding of the immunoregulatory mechanisms of oral tolerance which could potentially be used to control pathologic T cell- mediated immune responses.